Throughout this application various publications are referred to in brackets. Full citations for these references may be found at the end of the specification. The disclosures of these publications are hereby incorporated by reference in their entirety into the subject application to more fully describe the art to which the subject invention pertains.
Inflammation is the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli as well as initiate the healing process for the tissue. Inflammation can be classified as either acute or chronic. Acute inflammation is the initial response of the body to harmful stimuli and is achieved by the increased movement of plasma and leukocytes from the blood into the injured tissues. A cascade of biochemical events propagates and matures the inflammatory response, involving the local vascular system, the immune system, and various cells within the injured tissue.
Chronic inflammation progressively shifts the cells types present at the site of inflammation and is characterized by simultaneous destruction and healing of the tissue from the inflammatory process. Chronic inflammation in various tissues underlies a large group of diseases that include such inflammatory conditions as autoimmune diseases, inflammatory bowel disease, rheumatoid arthritis, endotoxemia, cancer, sepsis, atherosclerosis, vasculitis, transplant rejection, asthma, ischaemic heart disease, obesity-related insulin resistance and diabetes.
Obesity is a major risk factor for conditions ranging from metabolic syndrome and type 2 diabetes mellitus to atherosclerosis. Low grade inflammation leading to insulin resistance is a central feature of the pathophysiology of most obesity-related disorders. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. Increasing adiposity leads to inflammation and recruitment of immune cells to adipose tissue. The adipocyte itself is integral to the development of obesity-induced inflammation.
The innate immune response is driven primarily by signaling molecules collectively referred to as cytokines, which are used by cells of the immune system to communicate the integrity of the body's barriers to the environment. Cytokines are normally produced by immune cells in response to pathogen-associated molecules (PAMPs) or damage-associated molecules (DAMPs), and activate other immune cells to increase the body's immune response. There are two main classes of clinically relevant cytokines: pro-inflammatory mediators that activate and amplify inflammation and anti-inflammatory mediators that impede and balance the inflammatory response. A predominant belief amongst immunologists is that an unrestrained pro-inflammatory mediator cascade causes disease [1-11]. The dysregulated sequence of pro-inflammatory cytokines leading to disease has been referred to as a “cytokine storm” [12] or “inflammatory cascade” [13], as one cytokine typically leads to the production of multiple other cytokines to reinforce and amplify the immune response.
Pro-inflammatory mediators can be further broken down into two subgroups: early mediators and late mediators [1, 2, 15, 16]. Early mediators (tumor-necrosis factor, interleukin-1, interleukin-6, etc.) are not sufficient therapeutic targets for re-establishing homeostatic balance because they are resolved within the time frame of a patient's travel to a clinic to receive medical attention [1, 9-11, 14, 15]. Conversely, late mediators can be therapeutically targeted as they occur later in the “inflammatory cascade,” after a patient has realized that he or she has fallen ill.
The present invention provides a method for preventing or treating myriad diseases mediated by chronic inflammation.